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Berberine is characterized by its poorly gastrointestinal absorption and rather low bioavailability.Despite of the definite hypolipidemic effect following oral administration, the proposed mechanism can not well interpret the apparent contradiction between PK and PD.Our primary study of pharmacokinetics suggested that, in vivo berberine was too low to exert the therapeutic effect demonstrated in previous in vitro study, where berberine was trapped in gut content after the model hamsters were orally given with berberine.Meanwhile, although the exposure level of in-ragastric-administered berberine was much lower than that of intraperitoneal-administered berberine, it even had stronger lipid-lowing effect.Moreover, metabolomic study revealed that oral administration of berberine elevated the generation of bile acids, which failed to depress CYP7A1 by activating FXR signal pathway.